Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress

• Published in: Neuropharmacology 2020-01, Vol.162, p.107835, Article 107835
• Main Authors: Nozaki, Kanako, Ito, Hikaru, Ohgidani, Masahiro, Yamawaki, Yosuke, Sahin, Ezgi Hatice, Kitajima, Takashi, Katsumata, Seishi, Yamawaki, Shigeto, Kato, Takahiro A., Aizawa, Hidenori
• Format: Article
• Language: English
• Subjects: Amygdala - drug effects; Amygdala - metabolism; Animals; Antidepressive Agents - pharmacology; Anxiety - metabolism; Anxiety - psychology; Avoidance Learning - drug effects; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Cyclopropanes - pharmacology; Cytokines; Cytokines - drug effects; Cytokines - metabolism; Depression; Disease Models, Animal; Elevated Plus Maze Test; GABA-A Receptor Antagonists - pharmacology; Heterocyclic Compounds, 4 or More Rings - pharmacology; Hindlimb Suspension; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Lipopolysaccharides - toxicity; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Open Field Test; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, GABA - drug effects; Receptors, GABA - metabolism; Social Behavior; Social Defeat; Stress; Stress, Psychological - metabolism; Stress, Psychological - psychology; Translocator protein
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2019.107835

In preclinical models, it has been reported that social defeat stress activates microglial cells in the CNS. Translocator protein 18 kDa (TSPO) is a mitochondrial protein expressed on microglia in the CNS that has been proposed to be a useful biomarker for brain injury and inflammation. We hypothesized that a TSPO antagonist, ONO-2952, would inhibit the neuroinflammation induced by microglial hyperactivation and associated depressive-like behaviors. An in vitro analysis showed that ONO-2952 suppressed the release of pro-inflammatory cytokines and mitochondrial reactive oxygen species in cultured microglia stimulated by lipopolysaccharide. In mice submitted to chronic social defeat stress, microglia predominantly expressed TSPO in limbic areas implicated in depressive-like behaviors, including the amygdala, ventral hippocampus and nucleus accumbens, in which an increase in the production of pro-inflammatory cytokines in vivo were associated. Treating animals with ONO-2952 during chronic social defeat stress ameliorated impairments in social avoidance and anxiety-like behaviors and suppressed pro-inflammatory cytokine production, suggesting that ONO-2952 exerted an anti-stress effect in this animal model of depression. Thus, targeting TSPO as a candidate for the development of antidepressants that reduce susceptibility to chronic stress could pave the way toward therapeutic interventions for relapse prophylaxis in depression. [Display omitted] •Chronic stress induces TSPO expression in the limbic areas implicated in depression.•ONO-2952 suppresses cytokine expression induced in the limbic areas by chronic stress.•ONO-2952 inhibits cytokines and reactive oxygen species production in the cultured microglia.•ONO-2952 displays anti-anxiety and antidepressant effects.